Ras is involved in the negative control of autophagy through the class IPI3-kinase
Ras is involved in the negative control of autophagy through the class IPI3-kinase
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DOI：
10.1038/sj.onc.1207539
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发表时间：
2004-05-13
期刊：
影响因子：
8
通讯作者：
Kamata, T
中科院分区：
文献类型：
--
作者：
Furuta, S;Hidaka, E;Kamata, T
Ras蛋白在参与细胞增殖的信号转导中发挥关键的调节作用，其激活突变导致恶性细胞转化。然而，Ras蛋白在细胞生长控制中的细胞内蛋白质降解过程自噬中的作用是未知的。在本研究中，我们证明了NIH 3 T3细胞中的长寿蛋白质在营养饥饿反应中的降解被致癌RasVal 12转化以雷帕霉素（mTOR抑制剂）敏感的方式显着抑制。形态学观察还显示Ras转化后自噬泡形成减少。此外，表皮生长因子或血清下调血清饥饿诱导的蛋白质降解，而显性负性RasAsn 17突变体抵消了这种抑制作用，表明Ras介导了生长因子对自噬的下调。通过激活的RasVal 12对蛋白质降解的抑制是由I类磷脂酰肌醇3-激酶（PI 3-激酶）介导的，但不是由Raf Ral GDS或Raf Ral GDS介导的。与此相一致，RasVal 12和I类PI 3-激酶抑制LDH的自噬隔离速率。这些数据表明，Ras通过I类PI 3激酶信号通路作为营养缺乏诱导的自噬的负调节剂发挥关键作用。
Ras proteins exert a pivotal regulatory function in signal transduction involved in cell proliferation and their activation mutation leads to malignant cell transformation. However, the role of Ras proteins in autophagy, an intracellular protein degradation process in cell growth control is unknown. In the present study, we demonstrate that the degradation of long-lived proteins in NIH3T3 cells in response to nutrient starvation was significantly suppressed by oncogenic RasVal12 transformation in a rapamycin ( mTOR inhibitor)-sensitive manner. Morphologic observations also show the decrease in the formation of autophagic vacuoles upon the Ras transformation. Furthermore, epidermal growth factor or serum downregulated the protein degradation induced by serum starvation and the dominant-negative RasAsn17 mutant counteracted this suppressive effect, indicating that Ras mediates the growth factor downregulation of autophagy. The suppression of protein degradation by the activated RasVal12 was mediated by the class I phosphatidyl inositol 3-kinase (PI3-kinase), but not either or Raf Ral GDS. Consistent with this, RasVal12 and class I PI3-kinase inhibited the rate of autophagic sequestration of LDH. These data suggest that Ras plays a critical role as a negative regulator for nutrient deprivation-induced autophagy through the class I PI3-kinase signaling pathway.